KR910007365B1 - Preparation of benzoic acid derivatives having antimicrobial activity - Google Patents
Preparation of benzoic acid derivatives having antimicrobial activity Download PDFInfo
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Abstract
Description
본 발명은 하기 일반식 (I)의 벤조산 유도체의 제조방법에 관한 것이다.The present invention relates to a method for producing a benzoic acid derivative of the following general formula (I).
(상기 식중, A는 5 내지 10탄소원자를 갖는 직쇄 또는 측쇄알킬을 나타내고, X는 산소원자 또는 직접 결합을 나타내고, R은 수소원자, 또는 알콜기로 치환되어도 좋은 2 내지 6탄소원자를 갖는 알킬기를 나타낸다).(Wherein A represents a straight or branched chain alkyl having 5 to 10 carbon atoms, X represents an oxygen atom or a direct bond, and R represents a hydrogen atom or an alkyl group having 2 to 6 carbon atoms which may be substituted with an alcohol group) .
본 발명은 또한 일반식(I) 화합물의 염의 제조에 관한 것이다.The present invention also relates to the preparation of salts of compounds of general formula (I).
상기 화합물은 항세균활성을 나타내며, 특히 인체 및 가축용 방부제 또는 불활성 표면에 대한 살균제로서 사용될 수 있고, 또한 보존제로서 사용될 수 있다.The compounds exhibit antibacterial activity and can be used as antiseptics for human and animal preservatives or inert surfaces, and can also be used as preservatives.
X가 직접 결합을 나타내는 화합물(I)은 저널 어브 메디칼 캐미스트리, 1983, 제 26권, 페이지 335∼341에 기재된 방법에 따라 툴루산으로부터 제조될 수 있다.Compound (I) in which X represents a direct bond can be prepared from toluic acid according to the method described in Journal of Medical Chemistry, 1983, Vol. 26, pages 335-341.
상기 화합물은 또한 니트로페닐알카놀 또는 니트로페녹시알카놀(IV)로부터 제조될 수 있다. 화합물(IV)를 촉매 수소화 반응시킴으로써 대응 아닐린 유도체(V)가 수득되며, 기기에 산성 매질내에서 아질산 나트륨을 첨가함으로써 디아조늄이 수득된다. 샌드메이어의 반응에 의해 시안화 제일 구리와 반응시키면 벤조니트릴 유도체(VI)가 제조된다. 최종적으로 공지의 반응에 의해 화합물(I)을 합성하고 필요시 그의 적당한 염으로 전환시킨다.The compounds may also be prepared from nitrophenylalkanols or nitrophenoxyalkanols (IV). The corresponding aniline derivative (V) is obtained by catalytic hydrogenation of compound (IV), and diazonium is obtained by adding sodium nitrite in an acidic medium to the instrument. When benzonitrile derivative (VI) is produced by reacting with the first copper cyanide by the reaction of sandmeyer. Finally, compound (I) is synthesized by known reaction and converted to the appropriate salt thereof if necessary.
X가 직접 결합을 나타내는 경우 니트로페닐알카놀(IV)은 페닐알카놀(II)로부터 제조된다. 먼저 아세틸클로라이드를 사용해서 아세틸화 반응시킴으로써 히드록실기를 보호하고, 발연 질산으로 니트로화한 후 염화수소메탄올로 반응시켜서 알콜을 유리시킨다.Nitrophenylalkanol (IV) is prepared from phenylalkanol (II) when X represents a direct bond. The hydroxyl group is first protected by acetylation with acetyl chloride, nitrated with fuming nitric acid, and then reacted with hydrogen chloride methanol to liberate the alcohol.
페닐알카놀(II)는 직쇄 알콜을 포함하는 경우에는 시판용으로서 쉽게 구입할 수 있고, 그렇지 않을 경우에는 여러방법에 의해 제조될 수 있다. 예를 들어, 페닐아세트알데히드를 마그네슘 유도체와 반응시킨 다음 가수분해시킴으로써 2차 페닐알카놀이 제조된다.Phenylalkanol (II) can be easily purchased for commercial use in the case of containing a straight chain alcohol, or can be prepared by various methods. Secondary phenylalkanols are prepared, for example, by reacting phenylacetaldehyde with magnesium derivatives and then hydrolyzing it.
R1: 탄소원자 1내지 8을 갖는 알킬 1차 측쇄 페닐 알카놀은 시안화 벤질로부터 수득된다 :R 1 : Alkyl primary side chain phenyl alkanols having 1 to 8 carbon atoms are obtained from benzyl cyanide:
무수 매질내에서 수소화 나트륨을 반응시킨 후 알킬 브로마이드와 같은 알킬 할로게나이드를 첨가해서 대칭 디알킬화 페닐 아세토니트릴을 수득할 수 있다. 상기 화합물을 산으로 전환시키는 것은 알콜성 매질내에서 염기와 반응시킨 다음 산성화함으로써 수행된다.The symmetric dialkylated phenyl acetonitrile can be obtained by reacting sodium hydride in anhydrous medium and then adding alkyl halogenides such as alkyl bromide. The conversion of the compound to an acid is carried out by reaction with a base in an alcoholic medium followed by acidification.
피린딘 또는 디메틸아미노피리딘과 같은 촉매 존재하에 무수 매질내에서 티오닐 클로라이드 및 에틸 알콜을 차례로 반응시킴으로써 에틸 에스테르(VII)가 수득된다. 그 다음 무수 용매내에서 혼합 수소화물을 사용해서 환원시킴으로써 대응 알콜(II)"이 제조된다.Ethyl ester (VII) is obtained by sequentially reacting thionyl chloride and ethyl alcohol in anhydrous medium in the presence of a catalyst such as pyridine or dimethylaminopyridine. The corresponding alcohol (II) " is then prepared by reducing with a mixed hydride in anhydrous solvent.
X가 산소원자를 나타낼 경우 니트로페녹시알카놀(IV)는 니트로페놀(III)로부터 제조된다. 염기성 매질내에서 화합물(III)에 알킬 할로게나이드를 반응시키면 니트로페녹시알킬 할로게나이드(IX)을 수득한다.Nitrophenoxyalkanol (IV) is prepared from nitrophenol (III) when X represents an oxygen atom. Reaction of the alkyl halogenide with compound (III) in basic medium affords nitrophenoxyalkyl halogenide (IX).
이 생성물을 산성 매질내에서 아세틸화시킨 다음 비누화 반응시킴으로써 화합물(IV)을 유리시킨다.This product is acetylated in acidic medium and then saponified to liberate compound (IV).
모든 경우에 있어서, R이 알킬 또는 히드록시알킬인 화합물(I)은 표준 에스테르화 방법에 의해, 특히 촉매로서 강산 존재하에 산에 R - OH알콜을 작용시키거나 또는 산의 나트륨염에R-Hal할로게나이드를 작용시킴으로써 R이 H인 화합물(I)로부터 수득된다.In all cases, compound (I), wherein R is alkyl or hydroxyalkyl, is reacted by standard esterification methods, in particular in the presence of a strong acid as catalyst, to the acid or to the sodium salt of the acid R-Hal. It is obtained from compound (I) in which R is H by reacting the halogenide.
하기의 실시예는 본 발명을 설명하며, 본 발명을 한정하지는 않는다. 수득된 생성물이 오일 형태일 때는 내부 표준으로서 헥사메틸디실록산을 사용해서 중주소클로로포름내에서 60MHZ로 측정한 핵자기공명(NMR)스펙트럼으로 판별한다.The following examples illustrate the invention but do not limit the invention. When the obtained product is in the form of an oil, it is determined by nuclear magnetic resonance (NMR) spectrum measured by 60MH Z in mesochlorochloroform using hexamethyldisiloxane as an internal standard.
스펙트럼을 설명하기 위해 하기의 약어를 사용한다. : S단일선, D이중선, T삼중선, Q사중선, M다중선, J카플링 상수.The following abbreviations are used to describe the spectra. : S single line, D double line, T triplet, Q triplet, M multiline, and J coupling constants.
[실시예 1]Example 1
(히드록시 - 3 프로필) - 4 - 벤조산 : SR 41323(Hydroxy-3 propyl) -4-benzoic acid: SR 41323
(a) (니트로 - 4 페닐) - 3 - 프로판올 - 1(a) (nitro-4 phenyl) -3-propanol-1
95ml의 염화 아세틸을 171.5g의 페닐 - 3 프로판올 - 1 - 에 교반하에 1시간이내에 가한다. 이 혼합물을 환류하 2시간동안 가열하여 염산을 유리시키고 과량의 염화 아세틸을 제거한다. 반응 매질이 주위 온도로 환원되었을 때 이를 -25℃로 냉각된 800ml의 발연질산(d = 1.49)에 혼합하면서 적가한다. 온도를 -15 내지 -20℃로 유지하면서 1시간동안 계속 첨가한다. 그런 다음 혼합물을 얼음 조각을 함유한 1.5ι의 물에 가하고, 에테르로 세 번 추출하고, 물로 세 번, 10% 탄산나트륨 용액으로 세 번, 그리고 물로 세 번 세척한다. 에테르층을 황산마그네슘으로 건조시키고 검압하에 증발건조시킨다. 잔류물을 800ml의 메탄올에 혼합하고, 0℃에서 1시간동안 염산 기체로 발포시킨 다음 혼합물을 환규하에 14시간동안 가열한다. 용매를 증발시킨 후 잔류물을 물/에테르 혼합물에 혼합하고, 수성층을 물로 두 번, 중탄산나트륨 포화용액으로 세 번, 그리고 물로 세 번 세척한다. 에테르층은 황산마그네슘으로 건조시킨 다음 감압하에 증발 건조시킨다.95 ml of acetyl chloride are added to 171.5 g of phenyl-3 propanol-1 in 1 hour with stirring. The mixture is heated at reflux for 2 hours to liberate hydrochloric acid and remove excess acetyl chloride. When the reaction medium is reduced to ambient temperature it is added dropwise with mixing to 800 ml of fuming nitric acid (d = 1.49) cooled to -25 ° C. The addition is continued for 1 hour while maintaining the temperature between -15 and -20 ° C. The mixture is then added to 1.5ι water containing ice cubes, extracted three times with ether, washed three times with water, three times with 10% sodium carbonate solution, and three times with water. The ether layer is dried over magnesium sulfate and evaporated to dryness under pressure. The residue is mixed in 800 ml of methanol, foamed with hydrochloric acid gas at 0 ° C. for 1 hour and then the mixture is heated under circulating for 14 hours. After evaporation of the solvent the residue is mixed into a water / ether mixture and the aqueous layer is washed twice with water, three times with saturated sodium bicarbonate solution and three times with water. The ether layer is dried over magnesium sulfate and then evaporated to dryness under reduced pressure.
259g의 오랜지색 오일이 수득되며 클로로포름중에서 3Kg의 실리카겔로 크로마토그래피해서 정제한다.259 g of orange oil are obtained and purified by chromatography with 3 Kg silica gel in chloroform.
218g의 오랜지색 오일을 회수한다. 수율 95%.Recover 218 g of orange oil. Yield 95%.
(b) (히드록시 - 3 - 프로필) - 4 아닐린(b) (hydroxy-3 -propyl) -4 aniline
218g의 (니트로 - 4 페닐) - 3 프로판올 - 1을 500ml의 메탄올에 용해시키고, 미리 10ml의 물로 적신 석탄에 침착된 10%팔라듐 10g을 가한다. 40바아 압력하에 교반하면서 1시간 30분간 수소화 반응을 계속한다. 그런 다음 혼합물을 셀라이트에 여과하고, 메탄올로 씻고, 감압하에 증발 건조시켜서 168g의 갈색오일을 수득한다. 용리액으로 디클로로메탄을 사용해서 총 6Kg의 알루미나로 세 번 연속 크로마토그래피함으로써 정제한다. 49.2g의 연한 갈색 분말이 수득된다. Fc = 43 45℃, 수율 27%218 g of (nitro-4 phenyl) -3 propanol-1 are dissolved in 500 ml of methanol and 10 g of 10% palladium deposited on coal previously moistened with 10 ml of water is added. The hydrogenation reaction is continued for 1 hour and 30 minutes while stirring under 40 bar pressure. The mixture is then filtered through celite, washed with methanol and evaporated to dryness under reduced pressure to yield 168 g of brown oil. Purification by distillation using dichloromethane as eluent three consecutive chromatographys with a total of 6 Kg of alumina. 49.2 g of light brown powder are obtained. Fc = 43 45 ° C., yield 27%
(c) (히드록시 - 3 프로필) -4 벤조니트릴(c) (hydroxy-3 propyl) -4 benzonitrile
수득된 상기 생성물 49.07g을 400g의 얼음 조각을 함유하는 87ml의 진한 염산에 가한다. 온도를 0 내지 5℃로 유지하면서 8ml의 물에 23.15g의 아질산 나트륨을 용해시킨 용액을 적가한 다음 10분간 교반한 후 혼합물을 300ml의 10%탄산나트륨 수용액으로 중화시킨다.49.07 g of the obtained product is added to 87 ml of concentrated hydrochloric acid containing 400 g of ice cubes. A solution of 23.15 g of sodium nitrite dissolved in 8 ml of water was added dropwise while maintaining the temperature at 0 to 5 ° C, followed by stirring for 10 minutes, and then the mixture was neutralized with 300 ml of 10% aqueous sodium carbonate solution.
시안화 제일 구리 용액을 별도로 제조한다. 40.35g의 염화 제일 구리를 150ml의 물에 현탁시키고 거기에 54g의 시안화 나트륨을 80ml의 물에 녹인 용액을 가한다. 열 방출이 관찰되고 염화 제일 구리가 용해되며, 용액의 색이 사라진다. 용액을 0℃로 냉각시키고, 200ml의 벤젠을 가하고 0℃로 냉각된 디아조늄 용액을 40분간에 걸쳐 맹렬히 교반하면서 적가한다. 추가로 40분간 더 교반한 후, 교반하면서 주위 온도로 환원시키고, 그런 다음 교반하지 않으면서 50℃로 가열하고 주위 온도로 환원시킨다.The first copper cyanide solution is prepared separately. 40.35 g of cuprous chloride is suspended in 150 ml of water, and thereto is added a solution of 54 g of sodium cyanide dissolved in 80 ml of water. Heat release is observed, the cuprous chloride dissolves, and the color of the solution disappears. The solution is cooled to 0 ° C., 200 ml of benzene is added and the diazonium solution cooled to 0 ° C. is added dropwise with vigorous stirring over 40 minutes. After a further 40 minutes of stirring, the mixture is reduced to ambient temperature with stirring, then heated to 50 ° C. without stirring and reduced to ambient temperature.
에테르로 세 번 추출하고, 물로 두 번 그리고 염화 나트륨 포화용액으로 두 번 세척한다. 에테르층을 황산마그네슘으로 건조시키고 감압하에 증발 건조시킨다. 51g의 암갈색 오일을 수득한다. 용리액으로 톨루엔/ 에테르 혼합물(9/1, 부피/부피)을 사용해서 톨루엔내에서 1500g의 실리카겔로 크로마토그래피하여 정제한다. 41.6g의 순수한 생성물이 적색 오일 형태로 수득된다. 수율 79%Extract three times with ether, twice with water and twice with saturated sodium chloride solution. The ether layer is dried over magnesium sulfate and evaporated to dryness under reduced pressure. 51 g of dark brown oil is obtained. Purify by chromatography with 1500 g silica gel in toluene using a toluene / ether mixture (9/1, volume / volume) as eluent. 41.6 g of pure product are obtained in the form of a red oil. Yield 79%
생성물의 그의 NMR 스펙트럼으로 판별한다.It is determined by its NMR spectrum of the product.
2H : 1.7∼2.2ppm(M, - CH2- CH2- CH2- OH)2H: 1.7 to 2.2 ppm (M,-CH 2 -CH 2 -CH 2 -OH)
1H : 2.4ppm (S, - OH)1H: 2.4 ppm (S, -OH)
2H : 2.8ppm (T, J = 7HZ, CN - C6H4- CH2- CH2- )2H: 2.8 ppm (T, J = 7H Z , CN-C 6 H 4 -CH 2 -CH 2- )
2H : 3.6ppm (T, J = 6HZ- CH2- CH2- OH)2H: 3.6 ppm (T, J = 6H Z -CH 2 -CH 2 -OH)
2H : 7.3ppm (D, J = 9HZ, H 오르토 CH2)2H: 7.3 ppm (D, J = 9H Z , H ortho CH 2 )
2H : 7.6ppm (D, J = 9HZ, H 오르토 CN)2H: 7.6ppm (D, J = 9H Z , H Ortho CN)
(d) SR 41323(d) SR 41323
상기 생성물 41g을 150ml의 95%알콜에 용해시키고 15g의 가성 소다를 가한 다음 환류하에 17시간동안 교반하면서 가열한다. 냉각후 감압하에 증발 건조시키고, 잔류물은 물에 붓고 진한 염산으로 약 pH1까지 산성화시킨다. 에테르로 두 번 추출하고 물로 두 번 그리고 염화나트륨 포화용액으로 두 번 세척한다. 에테르층을 황산마그네슘으로 건조시키고 감압하에 증발 건조시킨다. 수득된 황색 결정을 에테르/헥산 혼합물로 재결정한다.41 g of the product are dissolved in 150 ml of 95% alcohol, 15 g of caustic soda is added and then heated under reflux for 17 hours with stirring. After cooling and evaporated to dryness under reduced pressure, the residue is poured into water and acidified to about pH 1 with concentrated hydrochloric acid. Extract twice with ether, twice with water and twice with saturated sodium chloride solution. The ether layer is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The yellow crystals obtained are recrystallized from an ether / hexane mixture.
33.7g의 크림색 분말이 수득된다. 융점 FC = 138∼141℃33.7 g of a cream colored powder are obtained. Melting Point FC = 138-141 ° C
[실시예 2]Example 2
에틸(히드록시 - 3 프로필) - 4 벤조에이트 : SR 41324Ethyl (hydroxy-3 propyl) -4 benzoate: SR 41324
수득된 생성물(SR 41323)13.5g을 200ml의 무수 에탄올에 용해시키고 6ml의 염화 티오닐을 교반하에 적가한다. 반응 매질이 주위 온도로 환원되었을 때 환류하에 6시간동안 교반하면서 가열한 다음 주위온도에서 밤새 방치한다. 용매를 감압하에 증발시키고, 혼합물을 에테르로 세 번 추출하고, 중탄산 나트륨 포화 용액으로 두 번, 물로 두 번 그리고 염화 나트륨 포화 용액으로 세척한다. 에테르층을 황산마그네슘으로 건조시키고 감압하에 증발 건조시킨다.13.5 g of the obtained product (SR 41323) are dissolved in 200 ml of absolute ethanol and 6 ml of thionyl chloride is added dropwise under stirring. When the reaction medium is reduced to ambient temperature, it is heated under reflux for 6 hours with stirring and then left overnight at ambient temperature. The solvent is evaporated under reduced pressure, the mixture is extracted three times with ether, washed twice with saturated sodium bicarbonate solution, twice with water and saturated sodium chloride solution. The ether layer is dried over magnesium sulfate and evaporated to dryness under reduced pressure.
15.43g 의 최종 생성물이 수득되며, 그의 NMR스펙트럼에 의해 판별한다 :15.43 g of final product are obtained, as determined by its NMR spectrum:
3H : 1.3ppm(T, J = 7HZ- CO2- CH2- CH3)3H: 1.3 ppm (T, J = 7H Z -CO 2 -CH 2 -CH 3 )
3H : 1.5∼2.2ppm(매시브, HO - CH2- CH2- CH2-)3H: 1.5 to 2.2 ppm (massive, HO-CH 2 -CH 2 -CH 2- )
2H : 2.7ppm(T, J = 7HZ, HO - CH2- CH2- CH2- C6H4)2H: 2.7 ppm (T, J = 7H Z , HO-CH 2 -CH 2 -CH 2 -C 6 H 4 )
2H : 3.6ppm(T, J = 6HZ, HO - CH2- CH2- CH2-)2H: 3.6 ppm (T, J = 6H Z , HO-CH 2 -CH 2 -CH 2- )
2H : 4.3ppm(Q, J = 7HZ, - CO2- CH2- CH3)2H: 4.3 ppm (Q, J = 7H Z ,-CO 2 -CH 2 -CH 3 )
2H : 7.2ppm(D, J = 9HZ, H 오르토 CH2)2H: 7.2 ppm (D, J = 9H Z , H ortho CH 2 )
2H : 7.9ppm(D, J = 9HZ, H 오르토 CO2)2H: 7.9 ppm (D, J = 9H Z , H ortho CO 2 )
[실시예 3]Example 3
(히드록시 - 2 부틸) - 4 벤조산 : CM 41074(Hydroxy-2 butyl) -4 benzoic acid: CM 41074
(a) 페닐 - 1 부탄올 - 2(a) phenyl-1 butanol-2
7.5ml의 에틸 브로마이드를 50ml의 무수에테르에 용해시킨 용액을 질소 기체하에 약하게 환류시킬 수 있을 정도의 비율로 2.92g의 마그네슘 티어닝에 적가한다. 계속 질소 기체하에 주위 온도에서 2시간동안 교반한 다음 9.4ml의 페닐아세트알데히드를 적가하고 교반하면서 주위 온도에서 2시간동안 방치한다.A solution of 7.5 ml of ethyl bromide dissolved in 50 ml of anhydrous ether is added dropwise to 2.92 g of magnesium tearing at a rate such that it can be slightly refluxed under nitrogen gas. Stirring was continued for 2 hours at ambient temperature under nitrogen gas, and then 9.4 ml of phenylacetaldehyde was added dropwise and left at ambient temperature for 2 hours with stirring.
0℃로 냉각된 20% 염화 암모늄 200ml로 분해시킨 다음 에테르로 세 번 추출한다. 물로 세 번 세척한 후 에테르층을 황산 마그네슘으로 건조시키고 감압하에 증발 건조시킨다. 12.2g의 약간 황색을 띠는 오일을 수득한다.Decompose with 200 ml of 20% ammonium chloride cooled to 0 ° C. and extract three times with ether. After washing three times with water, the ether layer is dried over magnesium sulfate and evaporated to dryness under reduced pressure. 12.2 g of slightly yellowish oil are obtained.
(b) CN 41074(b) CN 41074
실시예 1에 기재한 방법으로 CM 41074를 제조하고 에테르/헥산 혼합물로 재결정한다. Fc = 103∼106℃.CM 41074 is prepared by the method described in Example 1 and recrystallized from an ether / hexane mixture. Fc = 103-106 degreeC.
[실시예 4]Example 4
에틸(히드록시 - 2 부틸) - 4 벤조에이트 : CM 41075Ethyl (hydroxy-2 butyl) -4 benzoate: CM 41075
이 생성물은 산 CM 41074로부터 제조되며 그의 NMR스펙트럼에 의해 판별한다 :This product is prepared from acid CM 41074 and determined by its NMR spectrum:
3H : 0.9ppm(T, J = 7HZ, CH3- CH2- CH(OH) - CH2-)3H: 0.9 ppm (T, J = 7H Z , CH 3 -CH 2 -CH (OH)-CH 2- )
6H : 1.1∼1.7ppm(매시브, CH3- CH2- CH(OH), - CO2- CH2- CH3)6H: 1.1 to 1.7 ppm (massive, CH 3 -CH 2 -CH (OH),-CO 2 -CH 2 -CH 3 )
2H : 2.6∼2.9ppm(M, CH(OH) - CH2- C6H4-)2H: 2.6-2.9 ppm (M, CH (OH)-CH 2 -C 6 H 4- )
1H : 3.5∼3.9ppm(M, - CH2- CH(OH) - CH2)1H: 3.5-3.9 ppm (M, -CH 2 -CH (OH)-CH 2 )
2H : 4.3ppm(Q, J = 7HZ, - CO2- CH2- CH3)2H: 4.3 ppm (Q, J = 7H Z ,-CO 2 -CH 2 -CH 3 )
2H : 7.3ppm(D, J = 9HZ, H 오르토 CH2)2H: 7.3 ppm (D, J = 9H Z , H ortho CH 2 )
2H : 8ppm(D, J = 9HZ, H 오르토 CO2)2H: 8 ppm (D, J = 9H Z , H ortho CO 2 )
[실시예 5]Example 5
(히드록시 - 4 부틸옥시) - 4 벤조산 : CM 40841(Hydroxy-4 butyloxy) -4 benzoic acid: CM 40841
(a) (니트로 - 4 페녹시) -1, 브로모 - 4 부탄(a) (nitro-4 phenoxy) -1, bromo-4 butane
니트로 - 4 페놀을 275ml의 물에 용해시킨 용액에 83ml의 디브로모 - 1, 4 - 부탄을 가한다음 49.5ml의 10N 수산화 나트륨을 교반하면서 적가한다. 혼합물을 환류하에 교반하면서 24시간동안 가열한다.To a solution of nitro-4 phenol dissolved in 275 ml of water is added 83 ml of dibromo-1,4-butane and then added dropwise with stirring 49.5 ml of 10N sodium hydroxide. The mixture is heated for 24 hours with stirring under reflux.
냉각 후 에테르로 세 번 추출하고, 보통의 가성 소다로 여섯 번 그리고 물로 세 번 세척한다. 에테르층을 황산 나트륨으로 건조시키고 증발시킨 다음 불용성 물질을 여과한다. 여과액은 증발 건조시키고 잔류물을 진공(0.05mmHg)하에 뽑아낸다. 헥산내에서 재분한 후 결정을 수득하여 여과하고 헥산으로 세척하고 진공하에 전조기내에서 건조시킨다.After cooling it is extracted three times with ether, washed six times with ordinary caustic soda and three times with water. The ether layer is dried over sodium sulfate, evaporated and the insoluble material is filtered off. The filtrate is evaporated to dryness and the residue is drawn off in vacuo (0.05 mmHg). After redistribution in hexane, the crystals are obtained, filtered, washed with hexane and dried in a bath under vacuum.
75g의 반죽성 크램색 생성물을 수득한다. 수율 55%.75 g of pasty scrambled product is obtained. Yield 55%.
(b) (니트로 - 4 페녹시) - 1 아세틸옥시 - 4 부탄(b) (nitro-4 phenoxy) -1 acetyloxy-4 butane
상기 생성물 75g을 80ml의 빙초산에 용해시키고, 45g의 무수 아세트산 나트륨을 가하고 교반하면서 환류하에 15분간 가열한다. 반응 혼합물을 500ml의 에테르를 함유하는 1ι의 빙수에 붓고 고체 탄산나트륨을 사용해서 pH7.5로 중화시킨다. 에테르를 세 번 수출하고 물로 세 번 세척한 후, 에테르층을 황산마그네슘으로 건조시키고 증발 건조시키고, 잔류물을 진공하에 뽑아낸다.75 g of the product are dissolved in 80 ml of glacial acetic acid, 45 g of anhydrous sodium acetate is added and heated under reflux for 15 minutes with stirring. The reaction mixture is poured into 1ι ice water containing 500 ml of ether and neutralized to pH 7.5 with solid sodium carbonate. The ether is exported three times and washed three times with water, then the ether layer is dried over magnesium sulfate and evaporated to dryness and the residue is drawn off in vacuo.
70g의 오랜지색 오일이 수득된다. 수율 100%.70 g of orange oil are obtained. Yield 100%.
(c) (니트로 - 4 페녹시) - 1 부탄올 - 4(c) (nitro-4 phenoxy) -1 butanol-4
상기 생성물 70g을 300ml의 메탄올에 용해시키고 30ml의 10N수산화나트륨을 가하고 교반하면서 환류하에 4시간동안 가열한다. 메탄올을 증발시킨 후, 잔류물을 물/에테르 혼합물에 붓고 에테르로 세 번 추출하고 염화나트륨 포화용액으로 세 번 세척한다.70 g of the product are dissolved in 300 ml of methanol, 30 ml of 10N sodium hydroxide is added and heated under reflux for 4 hours with stirring. After evaporating the methanol, the residue is poured into a water / ether mixture, extracted three times with ether and washed three times with saturated sodium chloride solution.
에테르층을 황산마그네슘으로 건조시키고 증발 건조시킨다. 생성된 결정을 헥산내에서 제분하고 여과하여 헥산으로 세척한 다음 진공하에 건조기내에서 건조시킨다.The ether layer is dried over magnesium sulfate and evaporated to dryness. The resulting crystals are milled in hexane, filtered off, washed with hexane and dried in vacuo in a dryer.
48.8g의 약한 황색을 띠는 결정을 수득한다. Fc = 53∼55℃48.8 g of slightly yellowish crystals are obtained. Fc = 53-55 degreeC
(d) CM 40841(d) CM 40841
실시예 1에서와 같은 방법으로 하기 화합물을 제조한다 :The following compounds were prepared in the same manner as in Example 1:
(히드록시 - 4 부틸옥시) - 4 아닐린, Fc = 56∼58℃.(Hydroxy-4 butyloxy) -4 aniline, Fc = 56-58 degreeC.
(히드록시 - 4 부틸옥시) - 4 벤조니트릴, Fc 54∼58℃.(Hydroxy-4 butyloxy) -4 benzonitrile, Fc 54-58 degreeC.
CM 40841, Fc = 143∼145℃(에테르로 재결정한 후)CM 40841, Fc = 143-145 캜 (after recrystallization with ether)
본 발명의 방법과 유사한 제조방법에 의해 하기 표 1에 기재된 화합물이 제조된다. 에탄올/헥산 혼합물로 재결정한 후 그들의 NMR스펙트럼 또는 융점을 측정하여 판별한다.Compounds described in Table 1 are prepared by methods of preparation similar to those of the present invention. Recrystallization with an ethanol / hexane mixture is followed by determination of their NMR spectrum or melting point.
[표 1]TABLE 1
본 발명의 생성물의 NMR스펙트럼NMR spectrum of the product of the present invention
* SR 41709* SR 41709
9H : 1.1∼1.9ppm(매시브, HO - CH2- (CH2)3-CH2및 CO2- CH2- CH3)9H: 1.1 to 1.9 ppm (massive, HO-CH 2- (CH 2 ) 3 -CH 2 and CO 2 -CH 2 -CH 3 )
2H : 2.6ppm(T, J = 7HZ, - CH2- CH2- C6H4)2H: 2.6 ppm (T, J = 7H Z ,-CH 2 -CH 2 -C 6 H 4 )
2H : 3.6ppm(T, J = 6HZ, HO - CH2- CH2-)2H: 3.6 ppm (T, J = 6H Z , HO-CH 2 -CH 2- )
2H : 4.3ppm(Q, J = 7HZ, - CO2- CH2- CH3)2H: 4.3 ppm (Q, J = 7H Z ,-CO 2 -CH 2 -CH 3 )
2H : 7.2ppm(D, J = 9HZ, H 오르토 CH2)2H: 7.2 ppm (D, J = 9H Z , H ortho CH 2 )
2H : 8ppm(D, J = 9HZ, H 오르토 CO2)2H: 8 ppm (D, J = 9H Z , H ortho CO 2 )
* SR 41094* SR 41094
11H : 0.7∼1.7ppm(매시브, CH3- CH2- CH2- CH(OH), - CO2- CH2- CH3)11H: 0.7 to 1.7 ppm (massive, CH 3 -CH 2 -CH 2 -CH (OH),-CO 2 -CH 2 -CH 3 )
2H : 2.6∼2.9ppm(M, - CH(OH) - CH2- C6H4)2H: 2.6-2.9 ppm (M,-CH (OH)-CH 2 -C 6 H 4 )
1H : 3.6∼4ppm(M, - CH2- CH(OH) - CH2)1H: 3.6 to 4 ppm (M, -CH 2 -CH (OH)-CH 2 )
2H : 4.3ppm(Q, J = 7HZ, - CO2- CH2- CH3)2H: 4.3 ppm (Q, J = 7H Z ,-CO 2 -CH 2 -CH 3 )
2H : 7.3ppm(D, J = 9HZ, H 오르토 CH2)2H: 7.3 ppm (D, J = 9H Z , H ortho CH 2 )
2H : 8ppm(D, J = 9HZ, H 오르토 CO2)2H: 8 ppm (D, J = 9H Z , H ortho CO 2 )
* CM 40939* CM 40939
3H : 1.3ppm(T, J = 7HZ, CO2- CH2- CH3)3H: 1.3 ppm (T, J = 7H Z , CO 2 -CH 2 -CH 3 )
6H : 1.4∼1.9ppm(매시브, HO - CH2- CH2- CH2- CH2- CH2- O -)6H: 1.4-1.9 ppm (massive, HO-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -O-)
2H : 3.6ppm(T, J = 6HZ, CH2- CH2- O - C6H4)2H: 3.6 ppm (T, J = 6H Z , CH 2 -CH 2 -O-C 6 H 4 )
2H : 4ppm(T, J = 6HZ, HO - CH2- CH2-)2H: 4 ppm (T, J = 6H Z , HO-CH 2 -CH 2- )
2H : 4.3ppm(Q, J = 7HZ, CO2CH2CH3)2H: 4.3 ppm (Q, J = 7H Z , CO 2 CH 2 CH 3 )
2H : 6.9ppm(D, J = 9HZ, H 메타 CO2)2H: 6.9 ppm (D, J = 9H Z , H meta CO 2 )
2H : 8ppm(D, J = 9HZ, H 오르토 CO2)2H: 8 ppm (D, J = 9H Z , H ortho CO 2 )
본 발명의 생성물의 살균 활성을 하기의 방법으로 각종 균주에 대해 분석한다.The bactericidal activity of the product of the present invention is analyzed for various strains by the following method.
세균 접종물을 한정된 시간간격으로 시험 생성물의 각기 다른 희석액과 접촉시킨다. 접촉 말기에 세균 현탁액/생성물 혼합물 일부를 생성물의 항세균 작용을 중화시키는 물질을 함유하는 한천 배양 배지의 표면에 부착시킨다.The bacterial inoculum is contacted with different dilutions of the test product at defined time intervals. At the end of contact, a portion of the bacterial suspension / product mixture is attached to the surface of the agar culture medium containing a substance that neutralizes the antibacterial action of the product.
세균이 더 이상 자라지 않는 생성물 최소 농도를 살균 농도로 채택한다. 이 농도는 μg/ml로 나타낸다.The minimum concentration of product for which bacteria no longer grow is taken as the bactericidal concentration. This concentration is expressed in μg / ml.
조사용으로 선택된 세균 균주는 하기와 같다.Bacterial strains selected for investigation are as follows.
(1) 에스체리치아 콜리 CNCM 54125(1) Escherichia coli CNCM 54125
(2) 클래브시엘라 뉴모니아에 RO30 캡슐(2) RO30 capsule to Claebciella pneumoniae
(3) 슈도모나스 아에루기노사 CNCM A22(3) Pseudomonas aeruginosa CNCM A22
(4) 스트랩토코쿠스 파에칼리스 CNCM 5855(4) Straptococcus Paecalis CNCM 5855
(5) 스타필로코쿠스 아우레우스 CNCM 53154(5) Staphylococcus aureus CNCM 53154
두 번째 시험은 보르겔 페르구손(Worgel Fergusson)배지에 그리고 나머지는 트립 소이 아가 - 디프코(Tryptic Soy Agar - Difco, TSA)에서 수행한다.The second test is carried out on the Worgel Fergusson medium and the rest on Tryptic Soy Agar-Difco (TSA).
37℃에서 24시간 배양한 후, 유리구 및 증류수 1000ml당 트립톤 1g 및 염화나트륨 8.5g을 함유하는 희석액 10ml를 사용해서 세균 성장도를 측정한다. 제조된 현탁액을 교반하고 620nm에서의 광선 투과율을 분광 광도계로 측정한다.After 24 hours of incubation at 37 ° C., bacterial growth was measured using 10 ml of a dilution solution containing 1 g of tryptone and 8.5 g of sodium chloride per glass sphere and 1000 ml of distilled water. The prepared suspension is stirred and the light transmittance at 620 nm is measured with a spectrophotometer.
균주1 70%Strain 1 70%
균주2 80%Strain 2 80%
균주3 70%Strain 3 70%
균주4 60%Strain 4 60%
균주5 60%Strain 5 60%
세균 접종물은 상기 세균 현탁액의 1/20현택액에 해당된다.Bacterial inoculum corresponds to 1/20 suspension of the bacterial suspension.
컵이 달린 플레이트에 분석할 생성물의 각기 다른 희석액을 넣는다. 스티어스 (Steers)형태의 다위치 접종기를 사용해서 상기 희석액을 각기 다른 세균 현탁액과 접촉시킨다. 20분간 접촉시킨 후, 그 일부를 상기 접종기를 사용해서 활성 중화제, 즉 1000ml의 TSA(디프코)중의 20g의 루브롤 더블류(lubrol W), 2.5g의 트윈 80 및 2.5g의 티오황산 나트륨을 함유하는 페트리접시에 담긴 한천 배지(TSA)의 표면에 옮긴다. 분석할 생성물의 희석물 일부를 배양 배지 표면에 부착시킴으로써 각 시험 물질을 위한 중화제 효율 대조 기준을 만든다. 대응 접종물을 동일한 위치에 부착시킨다. 대조 접종물을 중화제를 포함한 한천 배지 및 중화제를 포함하지 않은 한천 배지에 만든다. 37℃에서 48시간 배양한 후 측정한다. 결과를 하기 표 2에 기재한다.In a cupped plate, add different dilutions of the product to be analyzed. The dilutions are contacted with different bacterial suspensions using a multi-position inoculator in the form of Steers. After contacting for 20 minutes, a portion of this was inoculated using the inoculator, ie 20 g of lubrol W, 2.5 g of Tween 80 and 2.5 g of sodium thiosulfate in 1000 ml of TSA (Diffco). Transfer to the surface of the agar medium (TSA) in the petri dish containing. A portion of the dilution of the product to be analyzed is attached to the culture medium surface to create a neutralizer efficiency control for each test substance. The corresponding inoculum is attached to the same location. Control inoculum is made in agar medium with neutralizer and agar medium without neutralizer. It is measured after incubation at 37 ° C. for 48 hours. The results are shown in Table 2 below.
[표 2]TABLE 2
결과적으로 본 발명의 생성물이 시험 세균 균주에 대해 광범위한 활성 스펙트럼을 나타냄을 알 수 있다.As a result, it can be seen that the product of the present invention exhibits a broad spectrum of activity against test bacterial strains.
본 발명 생성물의 항균 활성 역시 한천 배지에 연속적으로 희석시키는 방법으로 측정한다.The antimicrobial activity of the product of the present invention is also measured by the method of serial dilution in agar medium.
각종 생성물의 모액을 20% 테트라글리콜을 사용해서 만든다. 이 모액을 사용해서 동비 1/2의 등비 수열로 희석액을 만든다. 각 희석액 2ml를 패트리 접시에 담고 "사보우라우드 덱스트로오즈 한천"한천 배지(디프코) 1.8ml를 첨가한다. 효모용 접종물을 사보우라우드 액체 배지내에서 27℃로 48시간동안 배양시킨 1/20회석액으로 구성된다. 피부 생균류 및 오염물용 접종물은 5ml의 액체 사보우라우드 배지를 사용해서 사보우라우드 한천 배지내에서 배양물을 수거하여 제조한다.Mother liquors of various products are made using 20% tetraglycol. This mother liquor is used to make a dilution with an equal ratio of 1/2 of the ratio. 2 ml of each dilution is placed in a petri dish and 1.8 ml of "Savoloud Dextrose Agar" agar medium (Diffco) is added. The yeast inoculum consisted of 1/20 lime solution incubated for 48 hours at 27 ° C. in Savouroud liquid medium. Inoculations for skin live fungi and contaminants are prepared by harvesting the cultures in Savouroud agar medium using 5 ml of liquid Savouroud agar medium.
접종물을 다위치 접종기를 사용해서 패트리 접시의 표면에 부착시킨다. 효모의 경우는 27℃에서 48시간 배양한 후, 피부생균류의 경우는 27℃에서 7일간 배양한 후, 그리고 오염물의 경우는 27℃에서 4일간 배양한 후 각각 측정한다. 최소 억제 농도 또는 MIC(μg/ml)는 더 이상 성장이 일어나지 않는 최저 농도를 나타낸다.The inoculum is attached to the surface of the petri dish using a multi-position incubator. After yeast incubation for 48 hours at 27 ℃, incubation for 7 days at 27 ℃ for skin fungi, and 4 days at 27 ℃ for contaminants after each measurement. The minimum inhibitory concentration or MIC (μg / ml) represents the lowest concentration at which no further growth occurs.
표 3은 본 발명의 생성물 각각으로부터 수득된 결과를 제시한다.Table 3 shows the results obtained from each of the products of the present invention.
실험은 22효모 균주, 18피부 생균류 균주 및 18오염물 균주를 사용했다. 결과(MIC, μg/ml)는 각 부류에서 수득된 극단값을 나타낸 것이다.The experiment used 22 yeast strains, 18 skin live fungal strains and 18 contaminant strains. The results (MIC, μg / ml) represent the extremes obtained for each class.
[표 3]TABLE 3
상기 결과는 본 발명의 생성물이 분석된 균에 대해 우수한 활성을 나타냄을 보여준다.The results show that the product of the present invention shows excellent activity against the bacteria analyzed.
본 발명 생성물의 내성을 기니아 돼지로 분석한다. 돼지의 등의 정중선의 양쪽을 면도하고 다시 이틀마다 면도한다. 6마리씩 이루어진 군에 본 발명 생성물의 수성 또는 알콜성 용액 0.2ml를 면도한 부분에 투여한다. 생성불이 알콜성 용액 형태일때는 대조 동물군의 한쪽면에 알콜을 투여한다.The resistance of the product of the invention is analyzed with guinea pigs. Shave both sides of the pig's midline and again every 2 days. A group of six animals is administered to the shaved portion of 0.2 ml of an aqueous or alcoholic solution of the present invention. When the product is in the form of an alcoholic solution, alcohol is administered to one side of the control animal group.
사전의 피부 내성을 조사하기 위해서 3주 동안에 7일중 6일을 1일에 1번씩 처치한다. 피부를 관찰하면 홍반, 피부 발진 또는 각화증식증이 존재함이 발견되며, 그 세기를 소정의 단계에 따라 등급을 매긴다.To check for prior skin tolerance, 6 of 7 days are treated once a day for 3 weeks. Observation of the skin finds the presence of erythema, skin rash or keratosis, and its intensity is graded according to a predetermined stage.
피부 민감화 시험은 2주간 휴식시킨 후 동일한 동물에 대해 수행한다. 상기와 동일한 처치를 1주일간 수행한다. 동일한 기준 및 국부 내성에 사용한 것과 동일한 단계에 따라 평가한다.The skin sensitization test is performed on the same animal after 2 weeks of rest. The same treatment is performed for 1 week. Evaluate following the same criteria and same steps used for local tolerance.
또한 본 발명의 생성물이 기니아 돼지에 광독성 또는 광알레르기 효과를 나타내는지를 조사한다. Sciences et Tdchniques de l'Animal de Laboratoire 제 8권(3) 149∼160(1983)에 기재된 J. Unkovic, G. Mazue 및 J. Girard의 방법을 사용한다. Arch Dermatol,. 1967, 제 96권, 페이지 646-656에 기재된 L. C. Harber 씨들의 기술, 및 J. Soc. Cosm, Chem., 1966, 제 17권, 페이지 123-130에 기재된 L. J. Vinson씨들의 기술을 적용한다.It is also investigated whether the product of the invention exhibits phototoxic or photoallergic effects on guinea pigs. J. Unkovic, G. Mazue and J. Girard described in Sciences et Tdchniques de l'Animal de Laboratoire Vol. 8 (3) 149-160 (1983). Arch Dermatol ,. 1967, Vol. 96, page 646-656, by L. C. Harber, and J. Soc. The technique of L. J. Vinson, described in Cosm, Chem., 1966, Vol. 17, pages 123-130, is applied.
분석된 생성물은 모두 기니아 돼지에 있어서 열등한 내성, 민감화 효과 또는 광독성 또는 광 알레르기 효과를 나타내지는 않는다.The products analyzed do not all exhibit inferior resistance, sensitizing effects or phototoxic or photoallergic effects in guinea pigs.
급성 경구 독성의 평가는 쥐에게 수행한다. 이 시험은 L스리버 양육장에서 키운 CD1계 수컷 생쥐에 수행하며, 각 군은 체중 24∼30g의 5마리 생쥐로 이루어지고 동일한 우리에 넣는다.Evaluation of acute oral toxicity is performed in rats. This test is performed on CD1 male mice raised in L-Sriver nursery, each group consisting of 5 mice weighing 24-30 g and placed in the same cage.
동물을 처치전에 6시간동안 단식시키고, 각 시험을 위해 10%아리비아고무 용액에 현탁시킨 생성물을 식도탐침을 사용해서 강제로 투여한다.Animals are fasted for 6 hours prior to treatment and the product suspended in 10% ARIBA RUBBER SOLUTION for each test is forcibly administered using an esophageal probe.
강제 투여 4시간후 다시 동물에게 식이요법을 실시하고, 14일간 계속 관찰한다.Four hours after the forced administration, the animal is again dieted and continued for 14 days.
이 기간동안 각 실험군의 치사율을 조사하고 지능할 때마다 치사량 50(LD 50)을 리치질드 및 윌곡손 방법을 사용해서 측정한다.During this period, the lethality of each experimental group is investigated and each time the intelligence is determined, the lethal dose 50 (LD 50) is measured using the Richzide and Wilgoxon method.
하기의 결과가 수득되며 체중 kg당 시험물질의 mg으로 표시된다 :The following results are obtained and expressed in mg of test substance per kg of body weight:
CM 40937 LD 0＞3000CM 40937 LD 0 ＞ 3000
SR 41709 LD 0＞3000SR 41709 LD 0 ＞ 3000
CM 40939 LD 0＞3000CM 40939 LD 0 ＞ 3000
본 발명의 화합물은 흥미로운 활성도를 나타내며 이는 실제 사용되는 주요 방부제의 활성에 비교할 때 유리하다.The compounds of the present invention exhibit an interesting activity which is advantageous when compared to the activity of the main preservatives actually used.
덧붙여서, 본 발명의 생성물은 분석된 각종 세균종에 대해 균일한 활성을 나타낸다. 또한 낮은 독성 및 우수한 내성을 나타내며 민감화 효과, 광독성 또는 광 알레르기 효과는 전혀 나타내지 않는다.In addition, the products of the present invention exhibit uniform activity against the various bacterial species analyzed. It also exhibits low toxicity and good resistance and no sensitizing, phototoxic or allergic effects.
따라서, 본 발명의 생성물은 방부제, 보존제 및 살균제로서 널리 사용될 수 있다.Thus, the products of the present invention can be widely used as preservatives, preservatives and fungicides.
특히, 치료용 제제, 예를들어 농가진, 좌창, 감염 피부병, 감염된 열린 상처 및 부스럼, 표저, 농가진성음등과 같은 닫힌 감염을 치료하는 제제의 방부제로서 사용될 수 있다. 예방 목적으로 사용하는 것 역시 고려 할 수 있으며, 예를들면 외과 주변용 제제, 외과의사 또는 병원 직원의 손에 사용되는 제제가 있다.In particular, it can be used as a preservative for treating therapeutic agents, for example agents that treat impetigo, acne, infected skin diseases, infected open wounds and closed infections such as swells, bottoms, impetigo. Prophylactic use may also be contemplated, for example, preparations for surgical periphery, preparations for the hands of surgeons or hospital staff.
가축용으로 사용함에 있어서, 본 발명의 생성물은 방부제(예를들어 유방암의 예방) 또는 살균제(사육장 및 장비의 살균)로서 사용될 수 있으며 농업 - 식료품 분야에도 역시 사용할 수 있다.In use for livestock, the products of the invention can be used as preservatives (eg for the prevention of breast cancer) or as fungicides (sterilization of kennels and equipment) and also in the agriculture-foodstuff sector.
마지막으로 그들은 우수한 내성 및 낮은 독성을 갖기 때문에 약제 및 화장품 뿐 아니라 농업 - 식료품 분야에서도 보존제로서 사용될 수 있다.Finally, because of their good resistance and low toxicity, they can be used as preservatives not only in pharmaceuticals and cosmetics but also in agriculture-foodstuffs.
본 발명의 생성물의 각종 본초 약물 제제는 사용 목적에 따라 제조될 수 있다.Various herbal drug formulations of the products of the invention can be prepared according to the intended use.
[실시예 6]Example 6
방부성 알콜 용액Antiseptic alcohol solution
* SR 41945 0.5g* SR 41945 0.5g
* 알킬디메틸 카르복시메틸아민(30%용액) 0.5g* 0.5 g of alkyl dimethyl carboxymethylamine (30% solution)
* 에틸렌 옥시드 및 프로필렌 글리콜 L62의 축합물 1g* 1 g of condensate of ethylene oxide and propylene glycol L62
* pH6.5까지 첨가한 락트산 또는 수산화 나트륨Lactic acid or sodium hydroxide added up to pH6.5
* 70% 에틸알콜을 총량이 100g이 되도록 가한다.* Add 70% ethyl alcohol to 100 g total.
[실시예 7]Example 7
본 발명의 생성물은 샴푸 보존제로서 사용될 수 있다.The product of the present invention can be used as a shampoo preservative.
* 칼륨 및 아미노산 팔미테이트 20g20 g of potassium and amino acid palmitate
* 나트륨 알킬술페이트 2g2g sodium alkylsulfate
* 코푸라 디에탄올 이미드 5g* 5 g of Kopura diethanol imide
* 리놀릴 아세테이트 0.200g* Linoleyl Acetate 0.200g
* CM 40937 0.150g* CM 40937 0.150 g
* pH7까지 첨가한 수산화나트륨Sodium hydroxide added to pH7
* 정제수를 총량이 100g이 되도록 가한다.* Add purified water so that the total amount is 100g.
[실시예 8]Example 8
본 발명의 생성물은 유액 크림상테의 보존제로서 사용될 수 있다.The product of the present invention can be used as a preservative of the latex cream form.
* 진한 바셀린 오일 6g* 6g dark petrolatum oil
* 세토스테아릴 알콜 및 옥시메틸렌 세로스테아릴 알콜의 혼합물 9g* 9 g mixture of cetostearyl alcohol and oxymethylene serostaryl alcohol
* 무수 모노나트륨 포스페이트 0.300g0.300 g of anhydrous monosodium phosphate
* 디나트륨 테트라세메이트 0.010g* Disodium tetracemate 0.010g
* 바셀린 15g* 15 g of petroleum jelly
* CM 40937 0.100g* CM 40937 0.100g
* pH4.5까지 첨가한 인산* Phosphoric acid added up to pH4.5
* 정제수를 총량이 100g이 되도록 가한다.* Add purified water so that the total amount is 100g.
[실시예 9]Example 9
본 발명의 생성물은 미용 크림의 보존제로서 사용될 수 있다.The product of the present invention can be used as a preservative of cosmetic creams.
* 콜라겐 0.500g* Collagen 0.500g
* 카르복시폴리메틸렌 934 0.400g* Carboxypolymethylene 934 0.400g
* 경화리놀린 4g* Cured Linolin 4g
* 퍼히드로스쿠알렌 20g* Perhydrosqualene 20g
* 폴리옥시메틸화 소르비톨 모노팔미테이트 2g2g polyoxymethylated sorbitol monopalmitate
* SR 41709 0.150g* SR 41709 0.150g
* pH6.5까지 첨가한 락트산 또는 수산화나트륨Lactic acid or sodium hydroxide added up to pH6.5
* 정제수를 총량이 100g이 되도록 가한다.* Add purified water so that the total amount is 100g.
[실시예 10]Example 10
발포 세제액 방부 제제Foaming detergent preservative
* CM 40939 0.3g* CM 40939 0.3g
* 알칼디메틸카르복시메틸아민(30%용액) 15g* 15 g of alkaline dimethyl carboxymethylamine (30% solution)
* 디나트륨 테트라세메이트 0.1g0.1 g of disodium tetracemate
* 프로필렌 글리콜 20g20 g of propylene glycol
* pH5.8까지 첨가한 수산화나트륨Sodium hydroxide added up to pH5.8
* 정제수를 총량이 100g이 되도록 가한다.* Add purified water so that the total amount is 100g.
[실시예 11]Example 11
발포 세제액 방부 제제Foaming detergent preservative
* SR 41945 0.2g* SR 41945 0.2g
* 나트륨 술포네이트 파라핀 15gSodium sulfonate paraffin 15g
* pH5.2까지 첨가한 수산화나트륨 또는 락트산* sodium hydroxide or lactic acid added up to pH5.2
* 정제수를 총량이 100g이 되도록 가한다.* Add purified water so that the total amount is 100g.
[실시예 12]Example 12
불활성 표면용 살균제Disinfectants for Inert Surfaces
* SR 41709 0.5g* SR 41709 0.5g
* 도데실디메틸카르복시디메틸아민 20g* 20g of dodecyldimethylcarboxydimethylamine
* 디나트륨 테트라세메이트 2g2g disodium tetracemate
* pH 3.5까지 첨가한 락트산* Lactic acid added up to pH 3.5
* 정제수를 총량이 100g 이 되도록 가한다.* Add purified water so that the total amount is 100g.
[실시예 13]Example 13
과립 쥬스 또는 잼용 보존제Preservatives for Granulated Juice or Jam
* SR 41945 미분말 0.05g* SR 41945 fine powder 0.05g
[실시예 14]Example 14
크림용 보존제Cream Preservatives
* CM 40939 미분말 0.05g* CM 40939 fine powder 0.05g
Claims (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8313445 | 1983-08-18 | ||
| FR8313445A FR2550785B1 (en) | 1983-08-18 | 1983-08-18 | NOVEL COMPOSITIONS WITH ANTIMICROBIAL ACTIVITY CONTAINING BENZOIC ACID DERIVATIVES, THEIR PREPARATION METHOD, THEIR USE AS DISINFECTANT OR PRESERVATIVE DRUGS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR850001722A KR850001722A (en) | 1985-04-01 |
| KR910007365B1 true KR910007365B1 (en) | 1991-09-25 |
Family
ID=9291688
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019840004997A KR910007365B1 (en) | 1983-08-18 | 1984-08-18 | Preparation of benzoic acid derivatives having antimicrobial activity |
Country Status (24)
| Country | Link |
|---|---|
| US (2) | US4946868A (en) |
| EP (2) | EP0135433B1 (en) |
| JP (2) | JPS60120801A (en) |
| KR (1) | KR910007365B1 (en) |
| AT (1) | ATE34662T1 (en) |
| AU (2) | AU562423B2 (en) |
| CA (2) | CA1254226A (en) |
| CS (1) | CS244825B2 (en) |
| DD (1) | DD222005A5 (en) |
| DE (2) | DE3476160D1 (en) |
| DK (2) | DK387884A (en) |
| ES (1) | ES8505332A1 (en) |
| FI (1) | FI82237C (en) |
| FR (1) | FR2550785B1 (en) |
| GR (1) | GR80119B (en) |
| HU (1) | HU191944B (en) |
| IL (2) | IL72669A (en) |
| MA (1) | MA20205A1 (en) |
| NO (1) | NO158622C (en) |
| NZ (2) | NZ209264A (en) |
| PT (1) | PT79105B (en) |
| SU (1) | SU1296005A3 (en) |
| YU (1) | YU143184A (en) |
| ZA (2) | ZA846425B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3500972A1 (en) * | 1985-01-14 | 1986-07-17 | Henkel Kgaa | SEBOSUPPRESSIVE COSMETIC AGENTS, CONTAINING ALKOXY OR ALKYLBENZYLOXY BENZOESAEUREN OR THEIR SALTS |
| WO1993012782A1 (en) * | 1991-10-31 | 1993-07-08 | Elford Howard L | Method of treating viral diseases |
| DE4225794C2 (en) * | 1992-07-31 | 1994-12-08 | Schuelke & Mayr Gmbh | Tb-active carboxylic acids |
| DE4301295C2 (en) * | 1993-01-15 | 1999-04-08 | Schuelke & Mayr Gmbh | Aqueous disinfectant concentrate and disinfectant based on aldehyde and alcohol and their use |
| DE4447361A1 (en) * | 1994-12-21 | 1996-06-27 | Schuelke & Mayr Gmbh | Biocidal alcohols, their production and their use |
| CA2495923A1 (en) * | 2002-08-20 | 2004-03-04 | Doren M. Pinnell | Methods for treating fungal infections |
| AU2015214041B2 (en) | 2014-02-07 | 2018-12-06 | Gojo Industries, Inc. | Compositions and methods with efficacy against spores and other organisms |
| US9578879B1 (en) | 2014-02-07 | 2017-02-28 | Gojo Industries, Inc. | Compositions and methods having improved efficacy against spores and other organisms |
| GB2573933B (en) | 2017-01-31 | 2022-07-13 | Kimberly Clark Co | Antibacterial composition including benzoic acid ester and methods of inhibiting bacterial growth utilizing the same |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1050136A (en) * | ||||
| IL45396A0 (en) * | 1973-08-23 | 1974-11-29 | Beecham Group Ltd | Pharmaceutical compositions containing aryl aralkyl ether and thioether derivatives,certain such novel compounds and their preparation |
| US4016186A (en) * | 1973-11-27 | 1977-04-05 | Kyowa Hakko Kogyo Co., Ltd. | β-Phenoxy or substituted phenoxy ethanol compounds |
| GB1511645A (en) * | 1974-05-31 | 1978-05-24 | Univ Ife | Sickle cell anaemia treatment |
| US4433161A (en) * | 1982-03-08 | 1984-02-21 | Ethicon, Inc. | Methyl p-(ω-acetoxyalkoxy) benzoate and method of preparation |
-
1983
- 1983-08-18 FR FR8313445A patent/FR2550785B1/en not_active Expired
-
1984
- 1984-08-10 DK DK387884A patent/DK387884A/en not_active Application Discontinuation
- 1984-08-13 CS CS846115A patent/CS244825B2/en unknown
- 1984-08-13 ES ES535694A patent/ES8505332A1/en not_active Expired
- 1984-08-13 IL IL72669A patent/IL72669A/en unknown
- 1984-08-13 US US06/640,107 patent/US4946868A/en not_active Expired - Fee Related
- 1984-08-13 IL IL72668A patent/IL72668A/en unknown
- 1984-08-14 DK DK390384A patent/DK390384A/en not_active Application Discontinuation
- 1984-08-15 AU AU31947/84A patent/AU562423B2/en not_active Ceased
- 1984-08-15 AU AU31948/84A patent/AU565899B2/en not_active Ceased
- 1984-08-15 CA CA000461069A patent/CA1254226A/en not_active Expired
- 1984-08-15 CA CA000461070A patent/CA1271416A/en not_active Expired - Fee Related
- 1984-08-16 EP EP84401676A patent/EP0135433B1/en not_active Expired
- 1984-08-16 AT AT84401675T patent/ATE34662T1/en not_active IP Right Cessation
- 1984-08-16 DE DE8484401676T patent/DE3476160D1/en not_active Expired
- 1984-08-16 EP EP84401675A patent/EP0135432B1/en not_active Expired
- 1984-08-16 DE DE8484401675T patent/DE3471587D1/en not_active Expired
- 1984-08-16 GR GR80119A patent/GR80119B/en unknown
- 1984-08-17 ZA ZA846425A patent/ZA846425B/en unknown
- 1984-08-17 FI FI843264A patent/FI82237C/en not_active IP Right Cessation
- 1984-08-17 ZA ZA846424A patent/ZA846424B/en unknown
- 1984-08-17 SU SU843784979A patent/SU1296005A3/en active
- 1984-08-17 HU HU843125A patent/HU191944B/en not_active IP Right Cessation
- 1984-08-17 NO NO843296A patent/NO158622C/en unknown
- 1984-08-17 YU YU01431/84A patent/YU143184A/en unknown
- 1984-08-17 NZ NZ209264A patent/NZ209264A/en unknown
- 1984-08-17 NZ NZ209265A patent/NZ209265A/en unknown
- 1984-08-17 PT PT79105A patent/PT79105B/en not_active IP Right Cessation
- 1984-08-17 MA MA20429A patent/MA20205A1/en unknown
- 1984-08-18 KR KR1019840004997A patent/KR910007365B1/en active Search and Examination
- 1984-08-18 JP JP59172326A patent/JPS60120801A/en active Pending
- 1984-08-18 JP JP59172325A patent/JPS60166645A/en active Pending
- 1984-08-20 DD DD84266443A patent/DD222005A5/en not_active IP Right Cessation
-
1986
- 1986-01-07 US US06/816,978 patent/US4691043A/en not_active Expired - Fee Related
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